Determining how the epigenome serves as the interface between exercise and facilitated memory formation in the adult and aging female and male brain

Project Summary/Abstract Normal aging is accompanied by a decline in the capability to learn, form new memories and to retrieve previously established ones.

Given a steady increase in life expectancy in the United States, where 16% of the population consists of adults over the age of 65, the need for understanding the mechanisms by which behavioral interventions prevent cognitive decline or impairment in both normal aging individuals in addition to those with Alzheimer?s Disease (AD) are dire.

As observed from our lab and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic factor (BDNF).

Previous exercise experience enables a short, subthreshold exercise session, to again induce hippocampal BDNF in male mice, supporting the idea of a ?molecular memory window? for the previous exercise that facilitates later learning and memory consolidation.

Preliminary data in this proposal reveals that initial exercise establishes a ?molecular memory window?, enabling a short, subthreshold exercise session to facilitate learning and formation of long-term memory in situations usually subthreshold for encoding in adult (3-month old) male mice.

In a separate group of male mice, short, subthreshold exercise also facilitated synaptic plasticity in the hippocampus, including the regulation of synaptic structure and function genes only in mice with prior exercise experience.

The epigenome is able to incorporate prior experience (e.g. exercise) to form stable changes in cellular function, resulting in long-lasting behavioral adaptations.

Therefore, this proposal is focused on the concept that the epigenome serves as the interface between exercise and facilitated memory formation in the adult and aging female and male brain.

The overall hypothesis is that exercise creates a ?molecular memory? which is encoded via epigenetic mechanisms, allowing for facilitated long-term memory formation and synaptic plasticity in the adult and aging female and male brain.

Specific aims within this proposal will investigate the following in adult and aging females and males: Aim 1, determine exercise parameters that establish ?molecular memory windows?; Aim 2, examine the impact of exercise on synaptic plasticity; and Aim 3, Identify the gene expression networks and determine the epigenetic signature of the ?molecular memory window? for exercise.

Given that age is the strongest risk factor for Alzheimer?s Disease, our ability to use a novel approach and identify the epigenetic mechanisms underlying the capability of exercise to facilitate memory function will fundamentally impact all aging individuals of both sexes in the treatment and prevention of age-related cognitive decline or impairment.

This training fellowship will allow for development of molecular, physiology, and bioinformatics expertise. With the guidance of both Dr. Wood and Dr.

Cotman and the research and professional development environment at UCI, this fellowship will provide a foundation for a successful career as an independent investigator focused on understanding the epigenetic mechanisms underlying learning and memory in the female and male aging brain.